Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discovery
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.14/37224 |
Resumo: | New strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of Mycobacterium tuberculosis after macrophage phagocytosis is a fundamental step in the complex host–pathogen interactions that lead to granuloma formation and disease. Greater understanding of how the bacterium survives and thrives in these environments will inform novel drug and vaccine discovery programs. Here, we use in-depth RNA sequencing of Mycobacterium bovis BCG from human THP-1 macrophages to describe the mycobacterial adaptations to the intracellular environment. We identify 329 significantly differentially regulated genes, highlighting cholesterol catabolism, the methylcitrate cycle and iron homeostasis as important for mycobacteria inside macrophages. Examination of multi-functional gene families revealed that 35 PE/PPE genes and five cytochrome P450 genes were upregulated 24 h after infection, highlighting pathways of potential significance. Comparison of the intracellular transcriptome to gene essentiality and immunogenicity studies identified 15 potential targets that are both required for intracellular survival and induced on infection, and eight upregulated genes that have been demonstrated to be immunogenic in TB patients. Further insight into these new and established targets will support drug and vaccine development efforts. |
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Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discoveryBCGHost-pathogen interactionsMacrophageMycobacteriumRNAseqTranscriptomicsTuberculosisNew strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of Mycobacterium tuberculosis after macrophage phagocytosis is a fundamental step in the complex host–pathogen interactions that lead to granuloma formation and disease. Greater understanding of how the bacterium survives and thrives in these environments will inform novel drug and vaccine discovery programs. Here, we use in-depth RNA sequencing of Mycobacterium bovis BCG from human THP-1 macrophages to describe the mycobacterial adaptations to the intracellular environment. We identify 329 significantly differentially regulated genes, highlighting cholesterol catabolism, the methylcitrate cycle and iron homeostasis as important for mycobacteria inside macrophages. Examination of multi-functional gene families revealed that 35 PE/PPE genes and five cytochrome P450 genes were upregulated 24 h after infection, highlighting pathways of potential significance. Comparison of the intracellular transcriptome to gene essentiality and immunogenicity studies identified 15 potential targets that are both required for intracellular survival and induced on infection, and eight upregulated genes that have been demonstrated to be immunogenic in TB patients. Further insight into these new and established targets will support drug and vaccine development efforts.Veritati - Repositório Institucional da Universidade Católica PortuguesaMedley, JamieGoff, AaronBettencourt, Paulo J. G.Dare, MadelaineCole, LiamCantillon, DaireWaddell, Simon J.2022-04-01T10:11:31Z2022-01-132022-01-13T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.14/37224eng2076-393X10.3390/vaccines1001011385123238790PMC878027735062774000746680000001info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-01-23T01:41:50Zoai:repositorio.ucp.pt:10400.14/37224Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:30:16.422951Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discovery |
title |
Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discovery |
spellingShingle |
Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discovery Medley, Jamie BCG Host-pathogen interactions Macrophage Mycobacterium RNAseq Transcriptomics Tuberculosis |
title_short |
Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discovery |
title_full |
Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discovery |
title_fullStr |
Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discovery |
title_full_unstemmed |
Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discovery |
title_sort |
Dissecting the Mycobacterium bovis BCG response to macrophage infection to help prioritize targets for anti-tuberculosis drug and vaccine discovery |
author |
Medley, Jamie |
author_facet |
Medley, Jamie Goff, Aaron Bettencourt, Paulo J. G. Dare, Madelaine Cole, Liam Cantillon, Daire Waddell, Simon J. |
author_role |
author |
author2 |
Goff, Aaron Bettencourt, Paulo J. G. Dare, Madelaine Cole, Liam Cantillon, Daire Waddell, Simon J. |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Veritati - Repositório Institucional da Universidade Católica Portuguesa |
dc.contributor.author.fl_str_mv |
Medley, Jamie Goff, Aaron Bettencourt, Paulo J. G. Dare, Madelaine Cole, Liam Cantillon, Daire Waddell, Simon J. |
dc.subject.por.fl_str_mv |
BCG Host-pathogen interactions Macrophage Mycobacterium RNAseq Transcriptomics Tuberculosis |
topic |
BCG Host-pathogen interactions Macrophage Mycobacterium RNAseq Transcriptomics Tuberculosis |
description |
New strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of Mycobacterium tuberculosis after macrophage phagocytosis is a fundamental step in the complex host–pathogen interactions that lead to granuloma formation and disease. Greater understanding of how the bacterium survives and thrives in these environments will inform novel drug and vaccine discovery programs. Here, we use in-depth RNA sequencing of Mycobacterium bovis BCG from human THP-1 macrophages to describe the mycobacterial adaptations to the intracellular environment. We identify 329 significantly differentially regulated genes, highlighting cholesterol catabolism, the methylcitrate cycle and iron homeostasis as important for mycobacteria inside macrophages. Examination of multi-functional gene families revealed that 35 PE/PPE genes and five cytochrome P450 genes were upregulated 24 h after infection, highlighting pathways of potential significance. Comparison of the intracellular transcriptome to gene essentiality and immunogenicity studies identified 15 potential targets that are both required for intracellular survival and induced on infection, and eight upregulated genes that have been demonstrated to be immunogenic in TB patients. Further insight into these new and established targets will support drug and vaccine development efforts. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-04-01T10:11:31Z 2022-01-13 2022-01-13T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.14/37224 |
url |
http://hdl.handle.net/10400.14/37224 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2076-393X 10.3390/vaccines10010113 85123238790 PMC8780277 35062774 000746680000001 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799132024739463168 |